Acute myeloid leukemia (AML) is rapidly fatal, poorly controlled disease that can be rapidly brought into complete remission but where relapse kills the vast majority of patients. The genetic evolution of the disease has been defined retrospectively, but the basis for resistance to therapy and effective strategies to overcome it are lacking. This project seeks to take advantage of well-defined mouse models where a human leukemogenic allele induces highly penetrant, lethal AML that can be temporarily brought into remission by chemotherapy agents used in patients. Combining these basic biologic features with novel strategies for quantitatively assessing clonal behavior, clonal molecular features, physical localization and the in vivo parameters of growth pathway, cell cycle and apoptosis over time will provide multidimensional datasets for mathematical modeling of the parameters correlating with: 1. Clonal dominance in vivo (Specific Aim 1) and, 2. Sensitivity/resistance to chemotherapy in vivo (Specific Aim 2). The models will guide experimental testing of the role of the parameters in the in vivo behavior of the disease that will then be used to develop and test methods for enhancing durable control of AML (Specific Aim 3).